The persitence of amphetamine in rat brain for several hours produces long-term biochemical effects on striatal dopamine (DA) neurons including decreases in DA, 3,4-dihydroxyphenylacetic acid, homovanillic acid, tyrosine hydroxylase activity and the synaptosomal uptake of 3H-DA. This pattern of long-lasting biochemical effects suggests a neurotoxic effect and, consistent with this view, results from recent histochemical fluorescence and silver impregnation studies indicate damage of striatal DA nerve terminals in rats after multiple doses of methamphetamie. Elucidation of the mechanism of the neurotoxic effect of amphetamine on striatal DA neurons is of interest not only because of the persistent behavioral effects of the drug in man, but more importantly because indirect evidence suggests that DA itself may be the neurotoxic substance responsible for the neurotoxic effect. Studies are proposed to examine the dependence of amphetamine's striatal DA neurotoxicity on the biosynthesis of DA, to test the extent to which the chronic administration of dihydroxyphenylalanine or DA (intraventriculary) alone or in combination with an inhibitor of monoamine oxidase might produce long-lasting effects on striatal DA neurons similar to those of amphetamine and to test the extent to which other compounds which facilitate the release of DA will produce similar persistent neurochemical effects after their chronic administration. Other hypotheses to be tested include the possibility that the inhibition of striatal protein synthesis by amphetamine may play a role in its neurotoxic effect, the possibility that the presence of contiguous norepinephrine neurons may account for the relative insensitivity of extrastriatal DA neurons to amphetamine's neurotoxic effect, the possibility that the effect may result effect may result from the in vivo formation of a chemically active, highly electrophilic intermediate metabolite, and the possibility that striatal ascorbic acid may play a role in determining the sensitivity of striatal DA neurons to amphetamine's neurotoxic effect. In addition, since amphetamine reduces striatal blood flow, experiments are proposed to examine further the recent suggestion that DA neurons may be more sensitive to ischemic damage than other types of neurons. If this hypothesis is correct, then the neurotoxic effect of the drug on striatal DA neurons may reflect drug-induced ischemia sufficient to cause permanent damage specific to the relatively more sensitive DA neurons.